Estrogen Shapes Dopamine-Dependent Cognitive Processes: Implications for Women's Health

Abstract

Summary The prefrontal cortex (PFC) is exquisitely sensitive to its neurochemical environment. Minor fluctuations in cortical dopamine (DA) can profoundly alter working memory, a PFC-dependent cognitive function that supports an array of essential human behaviors. Dopamine’s action in the PFC follows an inverted U-shaped curve, where an optimal DA level results in maximal function and both insufficient or excessive DA impairs PFC function. In animals, 17-β estradiol (the major estrogen in most mammals, referred to henceforth as estradiol) has been shown to enhance DA activity, yet no human study has adequately addressed whether estradiol’s impact on cognition occurs by way of modulating specific neurochemical systems. Here, in healthy young women, we examined the effects of endogenous fluctuations in estradiol on working memory as a function of baseline PFC DA (indexed by COMT Val158Met genotype and, at a finer scale, COMT enzyme activity). The results demonstrate that estradiol status impacts working memory function and, crucially, the direction of the effect depends on indices of baseline DA. Moreover, consistent with a DA cortical efficiency hypothesis, functional MRI revealed that ‘optimal DA’ was associated with 1) reduced PFC activity sustained across task blocks 2) selectively enhanced PFC activity on trials with the greatest demand for cognitive control and 3) the magnitude of PFC activity during high control trials was predictive of an individual’s performance. These findings show that while estrogen, considered in isolation, may have unpredictable effects on cognitive performance, its influence is clarified when considered within a larger neuromodulatory framework. Given the clinical prevalence of dopaminergic drugs, understanding the relationship between estrogen and DA is essential for advancing women’s health.

High estradiol levels improve false memory rates and meta-memory in highly schizotypal women

“…In participants scoring high in cognitive disorganisation, high estradiol levels resulted in decreased confidence in false memories, while for participants scoring low on cognitive disorganisation, confidence in false memories was greater with higher estradiol levels. When considering meta-memory as a cognitive control process, the present data suggests that the beneficial effect of estradiol on cognitive control (Hjelmervik et al, 2012;Jacobs and D'Esposito, 2011;Keenan et al, 2001) might be specific to participants with high cognitive disorganisation, at least within the domain of memory.…”

“…However, it is currently unclear whether the effect of estrogen on memory occurs because of direct effects of estrogen on memory or rather via hormonal effects on memory control functions, such as meta-memory processes (Colzato et al, 2010). Indeed, it has been suggested that the enhancing effect of estrogen is particularly evident during tasks that demand a high level of (meta-) cognitive control, (Hjelmervik et al, 2012;Jacobs and D'Esposito, 2011). Given that meta-memory processes are conceptually comparable to cognitive control processes, it follows that meta-memory abilities should be enhanced under high estrogen conditions.…”

Estradiol and isotype-selective estrogen receptor agonists modulate the mesocortical dopaminergic system in gonadectomized female rats

“…From these findings we conclude that the transmission of reward signals to the PFC, in particular its dopaminergic component, is largely dependent on the gonadal hormone milieu, and E2 regulates dopamine availability mainly through the modulation of intracellular signaling pathways [55,58]. The tuning of dopamine levels has particular importance since dopamine effects follow a U-shaped dose-response curve in the PFC [57,59,60].…”

Lisdexamfetamine Effects on Executive Activation and Neurochemistry in Menopausal Women with Executive Function Difficulties

“…Proper executive functioning depends on the neurochemical environment of executive regions including the dorsolateral prefrontal cortex (DLPFC), the region of the prefrontal cortex (PFC) critical for attention and working memory (Arnsten and Jin, 2014). PFC function has been characterized as an inverted U-shaped curve such that optimal executive function (EF) depends on a balance of factors including baseline monoaminergic and glutamatergic function (Arnsten and Jin, 2014) as well as hormonal status (Jacobs and D'Esposito, 2011). In such a model, a decrease in estradiol levels during menopause could cause executive difficulties in women whose genetics or previous life experiences make them susceptible to such a cognitive decline (Culpepper, 2015;Kudielka et al, 2009;Shanmugan and Epperson, 2014) (Figure 1).…”

“…In women who metabolize dopamine more quickly, low estradiol levels result in improper PFC activation during working memory tasks (Jacobs and D'Esposito, 2011). Preclinical models have suggested estradiol modulation of glutamatergic function may be an additional mechanism by which estradiol loss induces changes in cognition.…”